Optically active esters such as alkyl 1,4-benzodioxan-2-carboxylates having a single chiral center adjacent to the carboxyl group have utility as precursors in the chemical synthesis of various pharmaceutical compounds. Resolution of the racemic ester mixtures into individual enantiomers provides a convenient point in the overall synthetic route to the corresponding optically pure pharmaceutical compound.
For example, doxazosin is an optically active pharmaceutical compound useful in the treatment of patients with hypertension, benign prostatic hyperplasia (BPH) and, perhaps, in the treatment of patients with elevated serum low density lipoprotein (LDL) levels. Doxazosin has the chemical structure (II) ##STR2## More specifically, doxazosin, the chemical name of which is 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquin azoline also known as 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxan-2 -yl)carbonyl] piperazine, is a quinazoline derivative having a single chiral center located on the carbon adjacent to the carboxyl group. This gives rise to a pair of enantiomers. However, doxazosin is currently commercially available only as the racemic mixture. However, it appears that administration of the optically pure (S)-(+)- enantiomer of doxazosin may provide the advantages associated with the administration of the racemic mixture without the accompanying adverse side effects. (See PCT application WO 94/09785). Isolation of the two enantiomers of doxazosin is therefore desirable.
Doxazosin has been resolved into its enantiomers on an analytical scale by Ley et al. See Recent Advances in Chiral Separations, Steven and Wilson Editors, Plenum Press, New York (1991) pages 97-103. However, there are no reports in the literature of a preparative-scale separation of the enantiomers. Thus, a need exists for a convenient and economic method for producing the enantiomers of racemic doxazosin which can be performed on a commercial scale.
The synthesis of doxazosin includes, as an intermediate step, the reaction of its optically active chemical precursor, ethyl 1,4-benzodioxan-2-carboxylate having the formula (III). ##STR3## Ethyl 1,4-benzodioxan-2-carboxylate has a chiral center adjacent to the carbonyl. Thus, resolution of the racemic mixture of this doxazosin precursor into isolated enantiomers would permit large-scale syntheses of the individual enantiomers of doxazosin. In particular, resolution of the ethyl (S)-1,4-benzodioxan-2-carboxylate or (S)-1,4-benzodioxan-2-carboxylic acid precursor would allow synthesis of the preferred S-enantiomer of doxazosin at a commercial level.
Resolution of racemic mixtures of chiral compounds can often be achieved by subjecting the mixture to the stereoselective action of various enzymes. Generally, enzymes for use in resolutions should exhibit a high degree of stereoselectivity for catalyzing the reaction of one isomer to the exclusion of others. For example, enzymatic resolution by enantioselective hydrolysis of various ester compounds has been widely employed for the lab-scale, preparative-scale, and industrial-scale production of many optically pure acids and esters.
One class of enzymes, the hydrolases, which includes lipases, proteases, esterases, trypsins, chymotrypsins, and dextranases, for example, is often used in the resolution of enantiomers because they are commercially available at reasonable cost, they do not require expensive cofactors, and some exhibit reasonable tolerance to organic solvents. Additionally, hydrolases are known to stereoselectively catalyze the hydrolysis of certain carboxylic acid derivatives, including esters.
However, resolution of the enantiomers of alkyl 1,4-benzodioxan-2-carboxylates by stereoselective enzymatic hydrolysis has not heretofore been described. Such a resolution is desirable in order to provide optically pure alkyl 1,4-benzodioxan-2-carboxylates and corresponding acids for use as synthetic precursors in the manufacture of pharmaceutical compounds, such as (S)-doxazosin.
Therefore, a need exists for an inexpensive and efficient method for producing on a commercial scale the individual enantiomers of alkyl 1,4-benzodioxan2-carboxylates.